Liver diseases related to the human hepatitis B virus (HBV) kill about 1 million people every year, and more than 350 million people around the world are infected with the virus. Some 15 million of these people are also infected with the hepatitis D virus (HDV), which is a satellite virus of HBV, and this places them at an even higher risk of liver diseases, including cancer. The viruses are known to enter liver cells by binding to receptors on their surface before being engulfed.
In an eLife study, published today, scientists have filled a major gap in our understanding of hepatitis B and D: they’ve identified the receptor that allows hepatitis B and hepatitis D viruses to enter human liver cells. The study could help in the development of new therapies and treatments for a disease that is carried by more than two billion people around the world. Hepatitis B virus (HBV) causes hepatitis and liver cirrhosis, and also increases the likelihood of liver cancer. Co-infection with hepatitis D virus (HDV) makes these conditions even worse.
In identifying the receptor (Sodium taurocholate cotransporting polypeptide or NTCP), Wenhui Li and co-workers from the National Institute of Biological Sciences in Beijing, Peking University, and Peking Union Medical College have overcome enormous technical challenges. Since HBV infects only humans, chimpanzees, and treeshrews – but not monkeys, rats, mice, or rabbits – they had to build and maintain a treeshrew “house” to produce the materials they needed. In an accompanying commentary article, Zhijian Chen and Jin Ye (UT Southwestern) say that the Chinese group performed “a tour de force series of experiments,” built a full record of all the RNA in treeshrew cells, and created a database of all their proteins – all enabling them to reach this breakthrough in hepatitis research.
The authors then performed a series of gene knockdown experiments on liver cells of both human and treeshrew origin: when the gene that codes for NTCP was silenced, HBV infection was greatly reduced. Moreover, they were able to transfect HepG2 cells—which are widely used in research into liver disease, but are not susceptible to HBV and HDV infection—with NTCP from humans and treeshrews to make them susceptible. Similarly, although monkeys are not susceptible to HBV, replacing just five amino acids in monkey NTCP with their human counterparts was enough to make the monkey NTCP a functional receptor for the viruses.
In the past, basic research into HBV and the development of antiviral therapeutics have both been hindered by the lack of suitable in vitro infection systems and animal models. Now, the work of Yan et al. means that it will be possible to use NTCP-complemented HepG2 cells for challenges as diverse as fundamental studies of basic viral entry/replication mechanisms and large-scale drug screening. It is also possible that HBV and HDV infection might interfere with some of the important physiological functions carried out by NTCP, so the latest work could also be of interest to medical scientists working on other diseases related to these infections.